Methotrexate action mechanism. Left panel represents the intervention of MTX in de novo pyrimidine synthesis, folate, and methionine pathways by the inhibition of key enzymes. Right panel shows the effect of MTX in de novo purine synthesis and adenosine pathway by ATIC inhibition. 5-MTHF: 5-methyltetrahydrofolate; 5,10-MTHF: 5,10-methylenetetrahydrofolate; ABC: ATP-binding cassette; ADORA: adenosine receptor; AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMP: adenosine monophosphate; ATIC: 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase; ATP: adenosine triphosphate; DHF: dihydrofolate; dTMP: deoxythymidine monophosphate; dUMP: deoxyuridine monophosphate; FAICAR: 5-formamidoimidazole-4-carboxamide ribonucleotide; IMP: inosine monophosphate; MTHFR: methylenetetrahydrofolate reductase; MTX: methotrexate; MTXPG: methotrexate polyglutamate; SLC: solute carrier; THF: tetrahydrofolate.